Endowing indole-based tubulin inhibitors with an anchor for derivatization: highly potent 3-substituted indolephenstatins and indoleisocombretastatins
| Autor: | Pilar Puebla, Manuel Medarde, Janis de la Iglesia-Vicente, José Manuel Andreu, Rafael Peláez, J. Fernando Díaz, Faustino Mollinedo, Raquel Álvarez, Rósula García-Navas, Ana C. Bento |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España), European Commission, Junta de Castilla y León, Ministerio de Asuntos Exteriores (España), Comunidad de Madrid, Red Temática de Investigación Cooperativa en Cáncer (España), Instituto de Salud Carlos III, Fundación Ramón Areces |
| Rok vydání: | 2013 |
| Předmět: |
Indoles
Molecular model Stereochemistry 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Cell Line Tumor Drug Discovery Humans Colchicine Cytotoxicity 030304 developmental biology Indole test 0303 health sciences biology 010405 organic chemistry Tubulin Modulators 0104 chemical sciences 3. Good health Tubulin Cell killing chemistry Cell culture biology.protein Molecular Medicine |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Journal of Medicinal Chemistry; Vol 56 |
| Popis: | Colchicine site ligands with indole B rings are potent tubulin polymerization inhibitors. Structural modifications at the indole 3-position of 1-methyl-5-indolyl-based isocombretastatins (1,1-diarylethenes) and phenstatins endowed them with anchors for further derivatization and resulted in highly potent compounds. The substituted derivatives displayed potent cytotoxicity against several human cancer cell lines due to tubulin inhibition, as shown by cell cycle analysis, confocal microscopy, and tubulin polymerization inhibitory activity studies and promoted cell killing mediated by caspase-3 activation. Binding at the colchicine site was confirmed by means of fluorescence measurements of MTC displacement. Molecular modeling suggests that the tropolone-binding region of the colchicine site of tubulin can adapt to hosting small polar substituents. Isocombretastatins accepted substitutions better than phenstatins, and the highest potencies were achieved for the cyano and hydroxyiminomethyl substituents, with TPI values in the submicromolar range and cytotoxicities in the subnanomolar range. A 3,4,5-trimethoxyphenyl ring usually afforded more potent derivatives than a 2,3,4-trimethoxyphenyl ring. This work was supported by Spanish MEC (ref CTQ2004-00369/BQU), the EU (Structural Funds), Spanish MICINN (SAF 2008-04242), the Consejeria de Educación de la Junta de Castilla y León (SA067A09), and the AECID (PCIMediterraneo A1/037364/11). Different parts of the work were performed on the basis of financial support from the Consejeria de Educación de la Junta de Castilla y León (Programa de Apoyo a Proyectos de Investigacion, EDU/940/2009, CSI052A11-2, and CSI221A12-2), Spanish Ministerio de Economia y Competitividad (BIO2010-16351, SAF2008-02251, SAF2011-30518), Comunidad de Madrid (S2010/BMD-2457 BIPEDD2 to JFD), Red Tematica de Investigación Cooperativa en Cancer, Instituto de Salud Carlos III, cofunded by the Fondo Europeo de Desarrollo Regional of the European Union (RD06/0020/1037 and RD12/0036/0065) and the European Community’s Seventh Framework Programme FP7- 2007-2013 (grant HEALTH-F2-2011-256986, PANACREAS). R.A. thanks the Spanish MEC for FPU and the Fundación Ramon Areces for a predoctoral grant. |
| Databáze: | OpenAIRE |
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